CN114452391A - Application of CDK16 as target in preparation of medicine for treating triple negative breast cancer - Google Patents
Application of CDK16 as target in preparation of medicine for treating triple negative breast cancer Download PDFInfo
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- CN114452391A CN114452391A CN202210104358.3A CN202210104358A CN114452391A CN 114452391 A CN114452391 A CN 114452391A CN 202210104358 A CN202210104358 A CN 202210104358A CN 114452391 A CN114452391 A CN 114452391A
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
The invention provides application of CDK16 serving as a target in preparation of a medicine for treating triple negative breast cancer. According to the invention, the knocking-down of CDK16 is found to be capable of obviously inhibiting the growth of TNBC xenograft tumor, PDX and PDO, and the mechanism is mainly that the knocking-down CDK16 is capable of inhibiting the phosphorylation of PRC1(T481), preventing the formation of cell mitotic spindle, enabling the cell not to normally divide, and further inhibiting the generation, development and metastasis of TNBC tumor. Meanwhile, the study finds that Rebastinib, a covalent small-molecule inhibitor of CDK16, has a very good effect on inhibiting the tumor development of TNBC, and is a potential novel drug for TNBC treatment.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of CDK16 as a target in preparation of a medicament for treating triple negative breast cancer.
Background
The breast cancer is the malignant tumor with the highest incidence rate in women at present, and seriously threatens the life health of the women. Triple Negative Breast Cancer (TNBC) refers to a breast cancer subtype in which Estrogen Receptor (ER), Progesterone Receptor (PR) and human epidermal growth factor receptor 2(HER2) are negative in a pathological staining report, which accounts for about 10% -15% of all breast cancers and is the most troublesome subtype in current breast cancer treatment. At present, the TNBC treatment lacks of targeted drugs, mainly chemotherapy, high mortality rate and easy relapse and metastasis, so that the search for a new effective TNBC treatment target is a problem to be solved urgently.
Therefore, there is a great need to develop effective TNBC therapeutic targets and drugs for the treatment of triple negative breast cancer.
Disclosure of Invention
The invention aims to provide application of CDK16 serving as a target in preparation of a medicament for treating triple negative breast cancer, and experiments show that a targeted CDK16 (knock-down) or CDK16 inhibitor can inhibit the generation, development and metastasis of TNBC tumors in TNBC tumor xenograft, PDX and PDO models.
In a first aspect of the invention, there is provided the use of CDK16 as a target in the preparation of a medicament for the treatment of triple negative breast cancer.
Further, the medicament for treating triple negative breast cancer is a medicament for inhibiting the occurrence, growth and metastasis of triple negative breast cancer.
Further, the medicament for treating triple negative breast cancer comprises at least one of the following components:
inhibitors of CDK 16;
a knockout agent for CDK 16.
Further, the CDK16 knockout agent is a drug that inhibits the in vitro proliferation of triple negative breast cancer cells, inhibits the growth of triple negative breast cancer xenograft tumors, PDX and PDO; the CDK16 inhibitor is a drug that inhibits the growth of triple negative breast cancer tumors.
Further, the CDK16 inhibitor comprises the small molecule inhibitor Rebastinib.
Further, the CDK16 knock-out agents comprise: the shRNA and/or gRNA of the target gene is targeted, and the nucleotide sequence of the shRNA is shown as SED ID NO.1-SED ID NO.2 or SED ID NO.3-SED ID NO.4 or SED ID NO.5-SED ID NO. 6.
In a second aspect of the invention, there is provided the use of a knockout agent of CDK16 or/and a CDK16 inhibitor in the preparation of a medicament for the treatment of triple negative breast cancer.
In a third aspect of the invention, there is provided a medicament for use in the treatment of triple negative breast cancer, the medicament comprising at least one of an inhibitor of CDK16 and a knock-out agent of CDK 16.
The medicine also comprises pharmaceutically acceptable auxiliary materials and carriers. The adjuvants include at least one of filler, disintegrant, binder, excipient, diluent, lubricant, sweetener or colorant. The dosage form of the medicine comprises at least one of granules, tablets, pills, capsules, injections or dispersing agents.
One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:
the invention provides application of CDK16 as a target in preparation of a medicament for treating triple-negative breast cancer, and researches show that the knocking-down of CDK16 can obviously inhibit the growth of TNBC xenograft tumor, PDX and PDO, and the mechanism of the CDK16 mainly comprises the steps of suppressing the phosphorylation of PRC1(T481) by knocking-down CDK16, preventing the formation of a cell mitotic spindle, preventing cells from normally dividing, and further inhibiting the generation, development and metastasis of TNBC tumor. Meanwhile, the study finds that Rebastinib, a covalent small-molecule inhibitor of CDK16, has a very good effect on inhibiting the tumor development of TNBC, and is a potential novel drug for TNBC treatment.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on the drawings without creative efforts.
FIG. 1 is a graph of CDK16 expression levels and clinical correlations among different clinical databases of breast cancer; wherein: FIG. 1A is the mRNA level of CDK16 in different types of breast cancer in the TCGA database; FIG. 1B is a graph relating CDK16 to overall patient survival; figure 1C is CDK16 associated with progression free survival of patients; FIG. 1D shows CDK16 correlated with disease-free survival of patients; fig. 1E, fig. 1F are mRNA levels and overall survival of CDK16 in different types of breast cancers in the METABRIC database; figure 1G is mRNA expression level of CDK16 in GSE76250 in normal tissue and TNBC; figure 1H is CDK16 protein expression levels in normal tissues and breast cancer in the CPTAC database;
FIG. 2 is a result of inhibition of TNBC cell line proliferation and resulting apoptosis in vitro after knock-down of CDK 16; wherein: fig. 2A is a graph showing that knock-down of CDK16 significantly inhibited TNBC cell line proliferation in vitro; fig. 2B shows that knock-down of CDK16 significantly promoted apoptosis in TNBC cell lines;
fig. 3 is a result of significant inhibition of growth of TNBC xenograft tumors, PDX and PDO after CDK16 was knocked down; wherein: FIG. 3A is a graph showing that knockdown of CDK16 significantly delayed MDA-MB-231 tumor development; FIG. 3B is a graph showing that knockdown of CDK16 significantly reduced the volume of MDA-MB-231 tumors; FIGS. 3C, 3D show that knocking down CDK16 significantly reduced the weight and size of MDA-MB-231 tumors; fig. 3E is a knock-down CDK16 significantly reducing the size and number of TNBC-type PDOs; fig. 3F is a graph showing that knock-down of CDK16 significantly inhibited the proliferation of TNBC-type PDO; fig. 3G is a knock-down of CDK16 significantly delayed the development of TNBC-type PDX tumors; fig. 3H is a graph of knock-down of CDK16 significantly reduced the volume of TNBC-type PDX tumors; fig. 3I, 3J knockdown CDK16 significantly reduced the weight and size of TNBC-type PDX tumors;
fig. 4 is a result of knock-down of CDK16 to inhibit TNBC metastasis and overexpression of CDK16 to promote TNBC metastasis; wherein: FIG. 4A is a panel showing that knockdown of CDK16 inhibits systemic metastasis of 4T1 cells; FIG. 4B is a graph showing that overexpression of CDK16 promotes systemic transfer of EMT6 cells;
fig. 5 is a result of the CDK16 small molecule inhibitor Rebastinib significantly inhibiting the growth of TNBC xenograft tumors, PDX and PDO; wherein: FIGS. 5A, 5B, 5C, 5D show that Rebatinib significantly inhibited the size, weight and size of MDA-MB-231 tumors; FIG. 5E is the size of PDO that Rebastinib significantly inhibited TNBC type; FIG. 5F shows that Rebatinib significantly reduced the number of TNBC type PDOs; fig. 5G shows that Rebastinib significantly inhibited the proliferation of TNBC-type PDO, promoting the apoptosis of TNBC-type PDO; fig. 5H, 5I, 5J, 5K are the volume, weight and size of PDX tumors of the TNBC type significantly inhibited by Rebastinib.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be obtained by an existing method.
In order to solve the technical problems, the general idea of the embodiment of the application is as follows:
the first part is that CDK16 is knocked down in TNBC tumor cells (MDA-MB-231, PDX and PDO), and the knocking-down CDK16 can obviously inhibit the generation and development of TNBC tumors through in-vitro 3D culture and in-vivo tumor formation experiments.
The second part is that in TNBC tumor xenograft, PDO and PDX models, Rebastinib, a small molecule inhibitor of CDK16, was found to significantly inhibit TNBC tumor growth.
The use of CDK16 of the present application as a target in the preparation of a medicament for the treatment of triple negative breast cancer will now be described in detail with reference to the examples and experimental data.
Example 1 knock-down of CDK16 in TNBC tumor cells and investigation of tumor progression in tumor cell line xenograft, PDX and PDO models
1. Vector construction
(1)shRNA
(ii) Scramble shRNA (as a negative control group for interference):
sense strand:
5'-CCGGCAACAAGATGAAGAGCACCAACTCGAGTTGGTGCTCTTCATCTTGTTGTTTTTG-3' (SED ID NO.7)
antisense strand:
5'-AATTCAAAAACAACAAGATGAAGAGCACCAACTCGAGTTGGTGCTCTTCATCTTGTTG-3' (SED ID NO.8)
②CDK16-shRNA-1:
sense strand:
5'-CGGGACCTACATTAAGCTGGACAACTCGAGTTGTCCAGCTTAATGTAGGTCTTTTTG-3'(SED ID NO.1)
antisense strand:
5'-AATTCAAAAAGACCTACATTAAGCTGGACAACTCGAGTTGTCCAGCTTAATGTAGGTC-3' (SED ID NO.2)
③CDK16-shRNA-2:
sense strand:
5'-CCGGCGAGGAGTTCAAGACATACAACTCGAGTTGTATGTCTTGAACTCCTCGTTTTTG-3' (SED ID NO.3)
antisense strand:
5'-AATTCAAAAACGAGGAGTTCAAGACATACAACTCGAGTTGTATGTCTTGAACTCCTCG-3' (SED ID NO.4)
④CDK16-shRNA-3:
sense strand:
5'-CCGGGCTCTCATCACTCCTTCACTTCTCGAGAAGTGAAGGAGTGATGAGAGCTTTTTG-3' (SED ID NO.5)
antisense strand:
5'-AATTCAAAAAGCTCTCATCACTCCTTCACTTCTCGAGAAGTGAAGGAGTGATGAGAGC-3' (SED ID NO.6)
(2) annealing the sense strand and the antisense strand of each shRNA, inserting the annealed 58bp oligonucleotide double strand into a pLKO.1 vector (the pLKO.1 vector is subjected to double enzyme digestion linearization by EcoR1 and Age1, and then enzyme-linked) to obtain a shRNA knock-out plasmid of CDK16, wherein the pLKO.1 vector contains a GFP or mCherry gene sequence.
2. Lentiviral packaging and cell transduction
The plasmid was extracted using the DP118(Tiangen Biotech) kit. Packaging of lentiviruses was performed with HEK293T cells. The specific method comprises the following steps:
(1) HEK293T cells were plated on 10cm plates and cultured in DMEM complete medium to ensure that the cells reached 80% -90% confluence the next day of transfection;
(2) 20 mu G of vesicular stomatis virus G plasmid, pCMV-delta 8.9 packaging plasmid and target plasmid are added, and the weight ratio of the plasmid to the plasmid is 5: 3: 2 into 950 mul of Opti-MEM, adding 60 mul of PEI transfection reagent after mixing evenly, shaking and mixing evenly again, and standing for 15 min;
(3) transfection of HEK293T cells: the plasmid is dropped into HEK293T culture solution evenly, the culture medium is sucked off after 6-8h, 10mL of fresh DMEM complete culture medium is added, then the culture is continued until transfection is carried out for 48 h, and cell supernatant is collected. After centrifugation at 4000rpm for 10min, the supernatant was filtered through a 0.45 μm filter to obtain a lentivirus solution.
(4) Lentivirus infection of tumor cells: for infection of a cell line, the cells are laid in a 6-well plate and cultured for 24h, the culture medium is sucked off after the cells are attached to the wall, the cells are changed into a lentivirus solution, the cells are changed into a fresh culture medium after 24h and continuously cultured for 24h, the fluorescence of the cells is observed under a fluorescence microscope, and positive cells are selected by a flow cytometer to establish line amplification for subsequent experiments. For infection of primary cells of a patient, primary tumor single cells are separated from tissues of the patient, the cells are paved in a 6-well plate or a culture dish, a lentivirus solution is added, after suspension infection is carried out for 24 hours, the cells are centrifugally collected, and positive cells are sorted out by a flow cytometer and used for construction of PDX or PDO.
3. In situ transplantation tumorigenesis of TNBC tumor cell line
Lentivirus-infected breast tumor cells were resuspended in 50% FBS (PBS dilution) at 1: 1, adding Matrigel, adding 0.04% trypan blue, mixing uniformly, and placing on ice until inoculating the mice. After anesthetizing, the mice were placed on a laboratory bench with their abdomen facing up and their abdomen epidermis was cut with scissors in the direction of the midline and the lower extremities to form a "Y" shaped opening (without cutting the peritoneum). Peel to both sides with a cotton swab and forceps, expose the 4 th pair of mammary fat pads and fix the epidermis with a needle. Sucking 10-20 μ L of cell suspension with a syringe, injecting into mammary gland fat pad, closing two sides of skin, suturing with surgical nail, and removing the surgical nail after wound healing. From the operation, the occurrence of tumor in the mice was observed and recorded every day. About one week or so, the length and width of the tumor was measured and recorded with a vernier caliper and the change in the body weight of the mice was monitored. Tumor volume was calculated by the following formula: volume (mm)3) Length × width × 0.52.
4. Construction of PDX model
Primary tumor cells from lentivirus infected patients were injected in situ into the fourth pair of mammary fat pads of NSG mice as described in 3, and tumor development was observed and recorded.
5. Establishment of PDO model
Primary tumor cells from lentivirus-infected patients were resuspended to a concentration of 2X 10 using a pre-cooled Matrigel4cells/50. mu.L Matrigel, adding the Matrigel dropwise into a 24-well culture plate, standing at 37 ℃ for 15-20min, adding a breast cancer tumor organoid culture medium after polymerization, culturing, replacing the fresh culture medium every three days, and counting the growth quantity and size of the organoids.
The results are shown in FIGS. 1-4;
as can be seen in fig. 1, CDK16 is highly expressed in breast cancer, particularly triple negative breast cancer, and is associated with clinical survival.
As can be seen from fig. 2, CDK16, when knocked down, inhibited TNBC cell line proliferation and caused apoptosis in vitro;
as can be seen from fig. 3, CDK16 was knocked down to significantly inhibit the growth of TNBC xenograft tumors, PDX and PDO;
as can be seen from fig. 4, knock-down of CDK16 inhibited TNBC metastasis and overexpression of CDK16 promoted TNBC metastasis.
Example 2 investigation of the inhibitory Effect of CDK16 inhibitor Rebastinib on tumor growth and metastasis
1. Rebatinib inhibition of MDA-MB-231 transplantable tumors and PDX growth
The same procedure as in example 1 was used to transplant the tumor cell line in situ until the tumor size reached 50cm3Mice were divided into a control group (solvent) and a Rebastinib administration group (80mg/kg), 3 mice per group, continuously gavage (MDA-MB-231 transplanted tumor was administered for 13 days, PDX was administered for 11 days), and the weight of the mice was weighed every day in the middle, the size of the tumor was measured every three days, and the tumor weight was weighed by killing the mice after completion of the administration.
2. Rebastinib inhibits TNB PDO growth
In analogy to the PDO modeling procedure in example 1, TNBC patient-derived primary tumor cells were resuspended in precooled MatrigelTo a concentration of 2X 104cells/50. mu.L Matrigel, dropping Matrigel into a 24-well culture plate, standing at 37 ℃ for 15-20min, adding a breast cancer tumor organoid culture medium after polymerization, culturing, replacing the fresh culture medium every three days, dividing PDO into 6 groups including an untreated group, a solvent control group, an Abemaciclib low and high dose group (the dose is 1. mu.M and 5. mu.M respectively) and a Rebastinib low and high dose group (the dose is 1. mu.M and 5. mu.M respectively), starting to treat according to groups after three days of PDO culture, and counting the size and the number of organoids after one week. The results are shown in FIG. 5;
as can be seen from fig. 5, Rebastinib, a small molecule inhibitor of CDK16, significantly inhibited the growth of TNBC xenograft tumors, PDX and PDO.
Finally, it should also be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
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Claims (8)
- Use of CDK16 as a target in the preparation of a medicament for the treatment of triple negative breast cancer.
- 2. The medicament of claim 1, wherein the medicament for treating triple negative breast cancer is a medicament for inhibiting the occurrence, growth and metastasis of triple negative breast cancer.
- 3. The use according to any one of claims 1-2, wherein the medicament for the treatment of triple negative breast cancer comprises at least one of the following components:inhibitors of CDK 16;a knock-out agent of CDK 16.
- 4. The use of claim 3, wherein the knockout agent of CDK16 is a medicament that inhibits in vitro proliferation of triple negative breast cancer cells, inhibits growth of triple negative breast cancer xenograft tumors, PDX, and PDO; the CDK16 inhibitor is a drug that inhibits the growth of triple negative breast cancer tumors.
- 5. The use according to claim 3, wherein said CDK16 inhibitor comprises the small molecule inhibitor Rebatib.
- 6. The use of claim 3, wherein the CDK16 knock-out agent comprises: the shRNA and/or gRNA of the target gene is targeted, and the nucleotide sequence of the shRNA is shown as SED ID NO.1-SED ID NO.2 or SED ID NO.3-SED ID NO.4 or SED ID NO.5-SED ID NO. 6.
- 7. Use of a knockout agent of CDK16 or/and a CDK16 inhibitor in the preparation of a medicament for treating triple negative breast cancer.
- 8. A medicament for use in the treatment of triple negative breast cancer, the medicament comprising at least one of an inhibitor of CDK16 and a knock-out agent of CDK 16.
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| CN202210104358.3A CN114452391B (en) | 2022-01-28 | 2022-01-28 | Application of CDK16 as target in preparation of medicine for treating triple negative breast cancer |
| PCT/CN2023/071088 WO2023142978A1 (en) | 2022-01-28 | 2023-01-06 | Use of cdk16 as target in preparation of medicine for treating triple-negative breast cancer |
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| WO2023142978A1 (en) * | 2022-01-28 | 2023-08-03 | 深圳市泰尔康生物医药科技有限公司 | Use of cdk16 as target in preparation of medicine for treating triple-negative breast cancer |
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| CN114452391B (en) * | 2022-01-28 | 2023-08-25 | 深圳市泰尔康生物医药科技有限公司 | Application of CDK16 as target in preparation of medicine for treating triple negative breast cancer |
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| CN114452391B (en) | 2023-08-25 |
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